Understanding Stem Cell Therapies: Education for Medical Professionals

1. PRESENTATION 2017

2. DISCLOSURE This presentation is intended for education purposes only and strictly for use by medical professionals. The FDA recently re-confirmed, there is only one registered stem cell product, and while there is enormous promise in stem cell therapies, and thousands of ongoing experimental applications trying to establish efficacy, these are not at the point where they would meet the scientific standard. The FDA has stated: Stem cells, like other medical products that are intended to treat, cure or prevent disease, generally require FDA approval before they can be marketed. FDA has not approved any stem cell-based products for use, other than cord blood-derived hematopoietic progenitor cells (blood forming stem cells) for certain indications. http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194655.htm This site is not intended for consumers. If you are considering stem cell treatment in the U.S., ask your physician if the necessary FDA approval has been obtained or if you will be part of an FDA-regulated clinical study. This also applies if the stem cells are your own. Even if the cells are yours, there are safety risks, including risks introduced when the cells are manipulated after removal. “There is a potential safety risk when you put cells in an area where they are not performing the same biological function as they were when in their original location in the body.” Cells in a different environment may multiply, form tumors, or may leave the site you put them in and migrate somewhere else. If you are considering having stem cell treatment in another country, learn all you can about regulations covering the products in that country. Exercise caution before undergoing treatment with a stem cell-based product in a country that—unlike the U.S.—may not require clinical studies designed to demonstrate that the product is safe and effective. FDA does not regulate stem cell treatments used solely in countries other than the United States and typically has little information about foreign establishments or their stem cell products. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm286155.htm Stem cell therapies have enormous promise, but the science in each use is still in the developmental stage.  Professional judgment and expertise is needed in using stem cells for any therapeutic use, and we urge anyone embarking on the use of stem cell therapies to consult the national health data bases to evaluate current information from clinical trials and the FDA websites on human tissue should also be consulted to get its current evaluation of any therapy.

3. https://www.cellmedicine.com TYPES Classification of available Stem Cell Therapies • Autograft: Derived from recipient’s own body. Usually derived from Adipose cells but can also come from bone marrow. • Allograft: Derived from another human and implanted and/or infused into another. Species to species • Xenograft: Different species

4. https://www.cellmedicine.com CordBloodStemCells All stem cells have 2 minimum qualities • Stems cells are renewable: They undergo mitosis and have the potential to double every 28 hours for up to as many as 90 generations. (In vitro) • Stem cells have potency: Potency is defined as the ability to differentiate into any cell in the body.

5. UmbilicalCordStemCellsHowTheyWork Damaged Cells: Put off a chemical signal in the space around them UC Cells: Attracted to the chemical signal Pericyte: Dock near the damaged cell through a lock and key/Ligand Receptor system Paracrine Signaling: Cell to cell communication in which the UC cells produce a signal to induce changes in a nearby cell, altering the behavior or differentiation of those cells. Trophic: Secrete cytokines and growth factors to direct cellular metabolism towards tissue regeneration working with the recipients own tissue to aid in the regenerative process

6. MAINCAPACITIES Anti-inflammatory: In musculoskeletal trauma, the body releases inflammatory molecules such as IL-1, IL-2, IL-12, TNF-alpha, and INF-gamma, all initiated by the T-1 helper cells.(Pro-inflammatory cells). MSC’s in response secrete an array of anti-inflammatory proteins and immunomodulatory cytokines including PGE-2, tissue growth factor beta-2 (TGF beta-2), hepatocyte growth factor (HGF), nitric oxide, IL-4, IL-6, IL-10, IL-1ra and many more, all initiated by the T-2 helper cells. (Anti-inflammatory cells)

7. MAINCAPACITIES Immunomodulatory: The key immunomodulatory cytokines include PGE 2, TGF Beta-1, HGF, SDF-1, nitrous oxide, indoleamine, 2,3-dioxygenase, IL-4, IL-6, IL-10, IL-1ra, and many more. Most autoimmune disorders are T-1 weighted (pro-inflammatory) and umbilical cord cells have the ability to rapidly modulate and balance the T-1/T-2 helper cells.

8. Main Capacities MAINCAPACITIESCONT’D Anti-apoptotic: Apoptosis-Programmed cell death, literally cell suicide. Umbilical cord cells have the ability to rescue apoptotic cells induced by trauma, exposure to hypoxia, chemicals/acidity, mechanical damage or radiation. Antimicrobial: MSC’s native immune defense against microbial infections is caused by multiple polypeptides. LL37 being the most common and has been shown to be effective against acute, chronic, and systemic infections. MSC’s have also been shown to be effective against protozoa. (Lyme’s disease)

9. SAFETY Mesenchymal stem cells produce huge quantities of bio-molecules, some of which are immunosuppressive; MSC’s put up a curtain of molecules around themselves that allows donor (allogenic) MSC’s to be transplanted into a recipient, free from an immune response. (Immune privileged/Immune Masked) While the body will naturally release TNF-a, IFN-y, IL-12 and T-1 helper cells to initiate an immune response from the allogenic stem cells, the MSC’s release IL-4, IL-10 and T-2 helper cells to effectively regulate the immune response. Arnold Caplan, PhD. Case Western Reserve University. Experimental and Molecular Medicine (2013) 45 Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine

10. ADVANTAGES Contains growth factors, proteins, and live nucleated cells that include stem cells Vs. Amniotic fluid/tissue that contains growth factors and proteins with very few, if any, live cells. Cellular component: MSC’s and HSC’s Endothelial progenitor cells • Fibroblasts (exists in all tissue) • Immune Cells (Regulatory T cells) FGF-2 Fibroblast growth factor PDGF- Platelet derived growth factor TGF-B Tissue growth factor beta • VEGF-Vascular endothelial growth factor NGF-Nerve growth factor

11. FUnction Medicinal Signaling Cell “This language is meant to recognize the ability of MSCs to have strong medicinal effects, while identifying that they do not exert their majority effects by regenerating tissue, but rather by leveraging sensory capabilities, positively affecting the microenvironment, and being sentinels for injury.” FDA held public hearing at the Masur Auditorium on the campus of the National Institutes of Health, in Bethesda, Maryland September 12-13, 2016

12. ADVANTAGESCONT’D • HUCT contains an abundant supply of MSC’s. • No need to collect stem cells through invasive procedures such as liposuction or bone marrow collection. • HUCT MSC’s proliferate/differentiate more efficiently than other types of stem cells and are therefore considered to be more potent. * Neil Riordan, Ph.D., Stem Cell Institute, Panama; ** Mehling, Quartararo, et al., Journal of Stem Cell Research, 2015, 5.8

13. RESEARCH • A search of www.clinicaltrials.gov website provides information on the more than 5,300 clinical trials being conducted worldwide.

14. TISSUEBANKREGULATIONS • Umbilical cords are considered a tissue and regulated by the AATB. (American Association of Tissue Banks) • All cells are rigorously tested for diseases, according to tissue bank regulations.

15. GUIDLINES • C.F.R. part 1271 Section 361 HCT/P’s. (Human Cells, Tissues, and Cellular and Tissue-Bases Products) • Be intended for homologous use as determined by labeling and advertising. • Be only minimally manipulated in manufacture. • Its manufacture not involve combination with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent (not raising new clinical safety concerns for the HCT/P). • Not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function or, if it has such an effect, it is intended for autologous use or allogeneic use in close relatives or for reproductive use.

16. THERAPEUTICS Autoimmune Disorders (122 known) • Rheumatoid Arthritis • Lupus • Discoid Lupus • Lupus nephritis • Interstitial Cystitis • Crohn’s disease • Autism • Cirrhosis • Alopecia Areata • Lichen Planus • CREST syndrome • Psoriasis • Scleroderma • Vitiligo • Addison’s dx • Grave’s dx • Sjogren’s • Endometriosis • Celiac dx • Ulcerative Colitis • Blood Disorders

17. THERAPEUTICSCONT’D • Lung Disease: COPD, Asthma, etc. • Diabetes Type II • Parkinson’s Disease • Alzheimer’s Disease • Stroke • Alcohol or Drug Addiction • ALS (Lou Gehrig’s dx) • Dermatological Conditions • Heart Disease • Osteoarthritis • Chronic Joint Pain • Low Back Pain • Bulging or Herniated Discs • Spinal Cord Injuries • Meniscus, ACL or MCL tears • Athletic Injuries • Erectile Dysfunction • Peyronie’s Disease

18. WOUND HEALING Wound Healing

19. WOUND HEALING Wound Healing

20. RHEUMATIOD ARTHRITIS LESIONS

21. RHEUMATIOD ARTHRITIS LESIONS